A Loss-of-Function Mutation in NaPi-IIa and Renal Fanconi's Syndrome

Magen, Daniella; Berger, Liron; Coady, Michael J.; Ilivitzki, Anat; Militianu, Daniela; Tieder, M; Selig, Sara; Lapointe, Jean‐Yves; Zelikovic, Israel; Skorecki, Karl

doi:10.1056/nejmoa0905647

Cited by 192 publications

(112 citation statements)

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“…However, multiple groups later questioned the pathogenicity of single heterozygous alleles in SLC34A1 (29)(30)(31). At this point, the pathogenicity of single heterozygous alleles in SLC34A1, as identified in five individuals with NL/NC in this study, cannot be clarified definitely.…”

Section: Discussionmentioning

confidence: 66%

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

Braun¹,

Lawson²,

Gee

et al. 2016

Clinical Journal of the American Society of Nephrology

117

110

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Background and objectives Nephrolithiasis is a prevalent condition that affects 10%-15% of adults in their lifetime. It is associated with high morbidity due to colicky pain, the necessity for surgical intervention, and sometimes progression to CKD. In recent years, multiple monogenic causes of nephrolithiasis and nephrocalcinosis have been identified. However, the prevalence of each monogenic gene in a pediatric renal stone cohort has not yet been extensively studied.Design, setting, participants, & measurements To determine the percentage of cases that can be explained molecularly by mutations in one of 30 known nephrolithiasis/nephrocalcinosis genes, we conducted a high-throughput exon sequencing analysis in an international cohort of 143 individuals ,18 years of age, with nephrolithiasis (n=123) or isolated nephrocalcinosis (n=20). Over 7 months, all eligible individuals at three renal stone clinics in the United States and Europe were approached for study participation.Results We detected likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 16.8% (24 of 143) of affected individuals; 12 of the 27 detected mutations were not previously described as disease causing (44.4%). We observed that in our cohort all individuals with infantile manifestation of nephrolithiasis or nephrocalcinosis had causative mutations in recessive rather than dominant monogenic genes. In individuals who manifested later in life, causative mutations in dominant genes were more frequent. ConclusionsWe present the first exclusively pediatric cohort examined for monogenic causes of nephrolithiasis/ nephrocalcinosis, and suggest that important therapeutic and preventative measures may result from mutational analysis in individuals with early manifestation of nephrolithiasis or nephrocalcinosis.

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Section: Discussionmentioning

confidence: 66%

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

Braun¹,

Lawson²,

Gee

et al. 2016

Clinical Journal of the American Society of Nephrology

117

110

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“…Both carried an in-frame duplication of 21 bp that was shown in Xenopus Laevis oocytes and opossum kidney cells to prevent transport of the protein to the cell membrane, thereby leading to complete loss-of function of the transporter [9]. The occurrence of Fanconi syndrome in the context of SLC34A1 mutation is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…It has remained unclear whether human heterozygous mutations may be the cause of kidney stones [7,8]. The clinical findings in the first reported homozygous NaPiIIa mutation in human included Fanconi syndrome and bone disease without hypercalciuria or nephroalcinosis [9], while another paper described hypercalcemia and nephrocalcinosis without skeletal dysfunction [10]. Recent publications strengthen the involvement of SLC34A1 in hypercalcemia and kidney stones.…”

Section: Introductionmentioning

confidence: 99%

Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency

et al. 2016

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BACKGROUND Inherited metabolic disorders associated with nephrocalcinosis are rare conditions. The aim of this study was to identify the genetic cause of an Israeli-Arab boy from a consanguineous family with severe nephrocalcinosis and kidney insufficiency. METHODS Clinical and biochemical data of the proband and family members were obtained from both previous and recent medical charts. Genomic DNA was isolated from peripheral blood cells. The coding sequence and splice sites of candidate genes (CYP24A1, CYP27B1, FGF23, KLOTHO, SLC34A3 and SLC34A1) were sequenced directly. Functional studies were performed in Xenopus laevis oocytes and in transfected opossum kidney (OK) cells. RE-SULTS Our patient was identified as having nephrocalcinosis in utero, and at the age of 16.5 years, he had kidney insufficiency but no bone disease. Genetic analysis revealed a novel homozygous missense mutation, Arg215Gln, in SLC34A1, which encodes the renal sodium phosphate cotransporter NaPiIIa. Functional studies of the Arg215Gln mutant revealed reduced transport activity in Xenopus laevis oocytes and increased intracellular cytoplasmic accumulation in OK cells. CONCLUSIONS Our findings show that dysfunction of the human NaPiIIa causes severe renal calcification that may eventually lead to reduced kidney function, rather than complications of phosphate loss.

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“…It is likewise unknown how therapy should be monitored, whether secondary hyperparathyroidism can develop as observed in FGF23-dependent hypophosphatemic disorders, 15 and whether phosphate requirements decrease with age, which has been reported for ADHR. 16 It will also be important to determine whether lack of the NPT2c transporter leads to additional symptoms, such as Fanconi syndrome or CKD, which have been shown for individuals with SLC34A1/NPT2a mutations, 14 using either animal models of HHRH or large HHRH kindreds, such as those kindreds described by Tieder et al 4,5 In summary, we here present five previously unreported HHRH kindreds and two individuals with IH in whom SLC34A3/NPT2c nucleotide sequence analysis identified known or novel mutations. Review of the clinical presentation of these kindreds and previously published HHRH kindreds suggests that renal calcifications and/or renal stones may be an important, often unrecognized initial symptom in carriers of comp/hom SLC34A3/NPT2c mutations.…”

Section: Serum 125(oh) 2 D Phosphate and Trp May Be Predictors Of mentioning

confidence: 99%

Mutations in SLC34A3/NPT2c Are Associated with Kidney Stones and Nephrocalcinosis

Dasgupta

Wee

Reyes

et al. 2014

Journal of the American Society of Nephrology

132

110

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Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na + )-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH) 2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P,0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH) 2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD.

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A Loss-of-Function Mutation in NaPi-IIa and Renal Fanconi's Syndrome

Cited by 192 publications

References 20 publications

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency

Mutations in SLC34A3/NPT2c Are Associated with Kidney Stones and Nephrocalcinosis

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